EBV(+) cancers represent a growing proportion of solid and hematogenous tumors, including Hodgkin's Disease, African Burkitt's lymphoma, Non- Hodgkin's lymphomas, lymphoproliferative disorders, nasopharyngeal carcinomas, gastric adenocarcinomas, and 20-50% of breast cancers. We have developed a novel therapy for these tumors, based on induction of the EBV thymidine kinase (TK) gene in latently-infected EBV(+) tumor cells by the experimental drug Arginine Butyrate. Induction of the viral TK gene by Arginine Butyrate and addition of the nucleoside antiviral ganciclovir (GCV) then leads to specific killing of virus-infected tumor cells, and spares normal cells. This IND-approved therapy has demonstrated safety in early trials, and efficacy in 5/7 patients with EBV(+) disease refractory to all other treatment modalities. Limitations to the use of Arginine Butyrate in this therapeutic setting are an extremely short in vivo half-life and the consequent need for continuous IV infusion necessitating prolonged hospitalization. This Phase I proposal will investigate orally-bioavailable, long half-lived butyrate derivatives to induce EBV-TK in tumor cells for use in combination with nucleoside analogue antivirals to treat EBV(+) malignancies. The result will be a novel, directed, therapeutic regimen for many types of cancer. PROPOSED COMMERCIAL APPLICATION: The therapy represents a novel and directed approach to treatment of many types of cancer. The individual drugs used are not cytotoxic chemotherapeutic agents and appear quite safe in extensive human testing to date. Unlike classical chemotherapy, this therapeutic strategy is selectively toxic towards only those (tumor) cells containing EBV. Because of its selectivity and safety, this therapy will represent a new approach to cancer treatment. The prototype drug is already in FDA- approved clinical testing.